Prostaglandin E2 induces growth inhibition, apoptosis and differentiation in T and B cell-derived acute lymphoblastic leukemia cell lines (CCRF-CEM and Nalm-6)

Despite advances in the treatment of ALL, in most patients long-term survival rates remain unsatisfactory. The objective of the present study was to investigate the anti-cancer effects of Prostaglandin E2 (PGE2) in two different ALL cell lines (CCRF-CEM (T-ALL) and Nalm-6 (B-ALL)). The anti-leukemic effects of PGE2 were also compared with two epigenetic compounds (trichostatin A and 5-aza-2'-deoxycytidine). MTT assay was used to assess growth inhibition by anti-cancer drugs in these cells. All three compounds were shown to induce apoptosis in both ALL cell lines using flow cytometry and Western blotting. To evaluate the differentiation induction by these agents, the expressions of CD19 and CD38 markers on Nalm-6 cell line and CD7 marker on CCRF-CEM cell line were assayed. Surprisingly, the flow cytometric analysis showed a significant increase in CD markers expression in response to PGE2 treatments. We, for the first time, provide evidences that PGE2 has anti-leukemic effects and induces differentiation at micromolar ranges in both T- and B-cell derived ALL cell lines. Since T-ALL cells are insensitive to current chemotherapies, these findings may help the designing of new protocols for T-ALL differentiation therapy in the future.     

Mast cell activation and autism

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social interactions, repetitive and stereotypic behaviors, as well as learning and sensory deficits. Despite the impressive rise in the prevalence of autism during the last two decades, there are few if any clues for its pathogenesis, early detection or treatment. Increasing evidence indicates high brain expression of pro-inflammatory cytokines and the presence of circulating antibodies against brain proteins. A number of papers, mostly based on parental reporting on their children's health problems, suggest that ASD children may present with “allergic-like” problems in the absence of elevated serum IgE and chronic urticaria. These findings suggest non-allergic mast cell activation, probably in response to environmental and stress triggers that could contribute to inflammation. In utero inflammation can lead to preterm labor and has itself been strongly associated with adverse neurodevelopmental outcomes. Premature babies have about four times higher risk of developing ASD and are also more vulnerable to infections, while delayed development of their gut-blood-brain barriers makes exposure to potential neurotoxins likely. Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Evaluation of Efficiency of Modified Polypropylenimine (PPI) with Alkyl Chains as Non-viral Vectors Used in Co-delivery of Doxorubicin and TRAIL Plasmid

In this study, co-delivery system was achieved via plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) and doxorubicin (DOX) using carrier based on polypropylenimine (PPI) modified with 10-bromodecanoic acid. Incorporation of alkylcarboxylate chain to PPIs (G4 and G5) could improve transfection efficiency via overcoming the plasma membrane barrier of the cells and decrease cytotoxicity of PPI. Characterization of fabricated NPs revealed that PPI G5 in which 30% of primary amines were substituted by alkyl carboxylate chain (PPI G5-Alkyl 30%) has higher drug loading as compared to the other formulations. PPI G5-Alkyl 30% indicated a decreased drug release may be due to alkyl chains on the surface of PPI, which serve as an additional hindrance for drug diffusion. In vitro cytotoxicity experiments demonstrated that co-delivery system induced apoptosis of tumor cells more efficiently than each of delivery system alone. Furthermore, these results revealed that our combined delivery platform of pTRAIL and DOX using Alkyl-modified PPI G5 can significantly improve the anti-tumor activity and this strategy might develop a new therapeutic window for cancer treatment.     

Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings

BACKGROUND: Malignant changes in pleomorphic adenoma (PA) of the salivary gland (carcinoma ex pleomorphic adenoma) are not common. Clear cell carcinoma is a rare form of salivary gland tumor and involves mostly minor salivary glands, especially those of the palate. Only 3 cases of clear cell carcinoma arising in PA have been reported, 2 in submandibular glands and 1 in a minor salivary gland of the palate. CASE : A 53-year-old man presented with an enlarged mass on the left side of the palate. He had a history of palate mass about 30 years earlier; it was excised and reported as PA. Since then the tumor had recurred twice in the same place; it had been excised and was diagnosed as PA again. A few years later the mass showed rapid growth over a few months. Fine needle aspiration of the mass showed epithelial clusters with bland nuclear features and myxohyaline material typical of PA. Also noted were large and small papillary, trabecular and well-circumscribed clusters of neoplastic cells with a moderate amount offoamy, vacuolated cytoplasm with distinct borders. Glandlike and acinar structures with hyaline globule material resembling cannonballs were also noted. The cytology was suspicious for malignancy. Incisional biopsy was reported as PA. Due to the suspicion of malignancy, the whole mass was excised up to the floor of the orbit. The final diagnosis was clear cell carcinoma expleomorphic adenoma. CONCLUSION: Due to nonspecific cytologic findings in clear cell carcinoma and a mixture of elements of PA in this case, we did not consider clear cell carcinoma as the malignant component.     

Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation

PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel ^−/−). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel ^−/− melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.     

Antibody-drug therapeutic conjugates: Potential of antibody-siRNAs in cancer therapy

Codelivery is a promising strategy of targeted delivery of cytotoxic drugs for eradicating tumor cells. This rapidly growing method of drug delivery uses a conjugate containing drug linked to a smart carrier. Both two parts usually have therapeutic properties on the tumor cells. Monoclonal antibodies and their derivatives, such as Fab, scFv, and bsAb due to targeting high potent have now been attractive candidates as drug targeting carrier systems. The success of some therapeutic agents like small interfering RNA (siRNA), a small noncoding RNAs, with having problems such as enzymatic degradation and rapid renal filtration need to an appropriate carrier. Therefore, the aim of this study is to review the recent enhancements in development of antibody drug conjugates (ADCs), especially antibody–siRNA conjugates (SRCs), its characterizations and mechanisms in innovative cancer therapy approaches.     

Sequencing analysis of SLX4/FANCP gene in Italian familial breast cancer cases

Breast cancer can be caused by germline mutations in several genes that are responsible for different hereditary cancer syndromes. Some of the genes causing the Fanconi anemia (FA) syndrome, such as BRCA2, BRIP1, PALB2, and RAD51C, are associated with high or moderate risk of developing breast cancer. Very recently, SLX4 has been established as a new FA gene raising the question of its implication in breast cancer risk. This study aimed at answering this question sequencing the entire coding region of SLX4 in 526 familial breast cancer cases from Italy. We found 81 different germline variants and none of these were clearly pathogenic. The statistical power of our sample size allows concluding that in Italy the frequency of carriers of truncating mutations of SLX4 may not exceed 0.6%. Our results indicate that testing for SLX4 germline mutations is unlikely to be relevant for the identification of individuals at risk of breast cancer, at least in the Italian population.     

Dirofilaria repens diagnosed by the presence of microfilariae in fine needle aspirates: a case report

BACKGROUND: Dirofilariasis due to Dirofilaria repens with viable microfilariae outside the worm have not been reported before. CASE: A 40-year-old truck driver from rural Shiraz, Iran, had a firm mass, 2.5 x 2.5 cm, at the dorsolateral aspect of the right forearm. Fine needle aspiration (FNA) was performed on 2 occasions. Several microfilariae with blunt heads, pointed posterior ends and empty caudal spaces resembling microfilariae of Wuchereria bancrofti but longer were seen. Since Iran is a nonendemic area for lymphatic filariae and the patient had a history of contact with a dog, with the impression of dirofilariasis, the mass was excised, and the presence of adult worms in tissue sections confirmed the diagnosis. CONCLUSION: This case ofsubcutaneous dirofilariasis was diagnosed by detecting microfilariae in FNA smears and was confirmed on histopathology.